SERENA-6 Splits the Breast Cancer Field on Switching Therapy Before Radiographic Progression: With Sara Nunnery, MD, MSCI; and Megan Kruse, MD

Breast Cancer Briefing, hosted by Sara Nunnery, MD, MSCI, a breast medical oncologist and the director of Breast Cancer Research at Tennessee Oncology in Nashville, is a podcast series that breaks down the latest news in breast cancer research, one conversation at a time.

In this episode, Nunnery sat down with Megan Kruse, MD, a breast medical oncologist at Cleveland Clinic in Ohio.

They discussed the phase 3 SERENA-6 trial (NCT04964934) and the controversy surrounding its novel, biomarker-driven switch strategy in patients with hormone receptor–positive, HER2-negative metastatic breast cancer. Central to the conversation was the ESR1 mutation, an acquired resistance mechanism that emerges under the pressure of endocrine therapy, typically after first-line metastatic treatment rather than in the adjuvant setting, Kruse explained. She noted that the mutation renders the estrogen receptor (ER) constitutively active, leaving it perpetually switched on so that aromatase inhibitors lose efficacy. Because these mutations develop over time, liquid biopsy is the preferred detection method, capturing the heterogeneity of multiple metastatic sites that a single tissue sample cannot, Kruse emphasized.

The experts contextualized why oral selective estrogen receptor degraders generate enthusiasm. Rather than merely blocking the receptor, they physically degrade it, producing activity regardless of ER conformation. In SERENA-6, patients with metastatic disease receiving a first-line aromatase inhibitor plus a CDK4/6 inhibitor for at least 6 months underwent circulating tumor DNA testing every 2 to 3 months; upon ESR1 mutation detection, they were randomly assigned in a double-blind fashion to continue their regimen or switch to camizestrant plus a CDK4/6 inhibitor. That this was an endocrine-sensitive patient population, Nunnery observed. The switch strategy improved median progression-free survival.

Kruse outlined the resulting controversy surrounding the trial, including the financial burden of serial testing, the absence of crossover, immature overall survival data, and the difficulty of interpreting time to second progression outcomes. The experts characterized camizestrant's safety as manageable. They concluded by noting that any future adoption of this camizestrant switch strategy in clinical practice will require individualized, patient-by-patient discussions.